Traditional non-targeted therapeutics circulate freely throughout the body of patients until removed from circulation. Such non-targeted molecules exert effects indiscriminately on a wide range of cells and tissues, which can cause serious side effects. When the therapeutic is toxic (e.g., a chemotherapeutic, where the “therapeutic window,” the difference between an efficacious and injurious or even lethal dose, is small), the problem is particularly acute.
Researchers have attempted to develop therapeutics specific for a particular tissue. Most target particular tissues by preferentially binding a target displayed by the tissue. By targeting diseased tissues, the therapeutic window it increased and side effects reduced.
Preferential binding is employed in antibody-directed enzyme prodrug therapy ((ADEPT); See, e.g., Xu et al., 2001, Clin Cancer Res. 7:3314-24; Denny, 2001, Eur J Med Chem. 36:577-95). In ADEPT, an antibody or antibody fragment is linked to an enzyme capable of converting an inactive prodrug into an active cytotoxic, producing an ADEPT conjugate. The conjugate is administered to the patient and localizes to a target tissue via antibody/antigen binding. An inactive prodrug is subsequently administered, and the prodrug circulates throughout the patient's body, but causes few or no side effects because the prodrug is inactive until activated by the conjugate only in the vicinity of the tissue. Thus, the therapeutic window of the toxin is increased at the desired site, as a relatively low concentration of active drug is present throughout the body, but a relatively high concentration of active drug is produced in the vicinity of the target tissue.
In ADEPT, selecting the proper antigen is important (e.g., an antigen that has a high tumor/normal expression profile). A tumor antigen of particular interest is TAG-72, frequently found on the cell surface in cancer tissues. TAG-72 is mainly a carbohydrate epitope expressed on a variety of human adenocarcinomas, but showing low expression in most normal tissues [Cao, Y., P. Stosiek, G. F. Springer and U. Karsten (1996) Histochem Cell Biol 106, 197-207, Thomsen-Friedenreich-related carbohydrate antigens in normal adult human tissues: a systematic and comparative study].